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US 2019/0194169 A1Published application
Novel pyrimidines as egfr inhibitors and methods of treating disorders
AssigneeDana-Farber Cancer Institute, Inc.
InventorsNathanael S. GRAY, Pasi JANNE, Hwan Geun CHOI, Jaebong JANG
Life of this patent
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Abstract
The application relates to a compound having Formula (I): which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.
Claims20
A method of inhibiting a kinase, inhibiting an epidermal growth factor (EGFR), or treating or preventing a disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I:
- or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
- Z1 and Z2 are each independently N and Z3 is CR8;
- R8 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
- R1 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, or halogen;
- R2 is H or (C1-C6) alkyl;
- R3 is (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
- R4 is NR9R10 or a 5- to 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
- R9 is H or (C1-C4) alkyl;
- R10 is (C1-C4) alkyl, (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1-C4) alkyl-N((C1-C4) alkyl)2;
- or R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
- each R11 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or halogen;
- R5 is NR12C(O)R13 or C(O)NR12R13;
- R12 is H or (C1-C6) alkyl;
- R13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2;
- R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula
- wherein
- X3 is N;
- X1, X2, X4, X5 and X6 are each independently CH or CR15;
- and
- each R15 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1-C6) alkyl, N((C1-C6) alkyl)2, or halogen.
17 more elements
A compound of Formula (I):
- or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
- Z1 and Z3 are each independently N and Z2 is CR8;
- R8 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
- R1 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, or halogen;
- R2 is H or (C1-C6) alkyl;
- R3 is (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
- R4 is NR9R10 or a 5- to 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
- R9 is H or (C1-C4) alkyl;
- R10 is (C1-C4) alkyl, (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1-C4) alkyl-N((C1-C4) alkyl)2;
- or R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
- each R11 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or halogen;
- R5 is NR12C(O)R13 or C(O)NR12R13;
- R12 is H or (C1-C6) alkyl;
- R13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2;
- R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic or heteroaryl ring optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R14;
- each R14 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1-C6) alkyl, N((C1-C6) alkyl)2, or halogen, or two R14 present on adjacent atoms together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heterocyclic or heteroaryl ring comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, heterocyclic, or heteroaryl is optionally substituted with one or more R15;
- and
- each R15 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1-C6) alkyl, N((C1-C6) alkyl)2, or halogen.
15 more elements
A compound of Formula (I):
- or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
- Z1, Z2, and Z3 are each independently N;
- R1 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, or halogen;
- R2 is H or (C1-C6) alkyl;
- R3 is (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
- R4 is NR9R10 or a 5- to 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
- R9 is H or (C1-C4) alkyl;
- R10 is (C1-C4) alkyl, (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1-C4) alkyl-N((C1-C4) alkyl)2;
- or R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
- each R11 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or halogen;
- R5 is NR12C(O)R13 or C(O)NR12R13;
- R12 is H or (C1-C6) alkyl;
- R13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2;
- R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic or heteroaryl ring optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R14;
- each R14 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1-C6) alkyl, N((C1-C6) alkyl)2, or halogen, or two R14 present on adjacent atoms together with the atoms to which they are attached form a phenyl ring or a 5- or 6-membered heterocyclic or heteroaryl ring comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, heterocyclic, or heteroaryl is optionally substituted with one or more R15;
- and
- each R15 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1-C6) alkyl, N((C1-C6) alkyl)2, or halogen.
14 more elements
Dependencies are inferred from the claim text.